Our long term goal is to understand the immunologic mechanisms that account for the wide spectrum of host immune responses to Wuchereria bancrofti and Brugia malayi, the causative agents of human lymphatic filariasis. The range of clinical manifestations is broad and considered to reflect intensity and type of immune responses to the parasite. Most residents of filarial endemic regions are asymptomatic and microfilaria- positive (MF) and generally considered immunologically hyporesponsive. In contrast, patients with intermittent lymphadenitis and lymphangitis leading to persistent lymphedema (CP) are amicrofilaremic but have strong cellular and humoral responses to the parasite. Our previous studies indicate that the basis for this altered immune responsiveness among MF subjects with W. bancrofti may result from several mechanisms: 1) a reduced frequency of antigen reactive T cell compared to CP patients; 2) active modulation by IL-10 and TGF-B; and 3) preferential production of IL-4 and IL-5 (Th2-like) by filarial Ag-reactive cells compared to a Th1- like response among CP individuals. Based on these observations and new preliminary results this proposal examines the hypothesis that asymptomatic MF individuals develop an Ag-specific tolerant state in which antigen presenting cells (APC) generate co-stimulatory signals that promote a Th2-like pattern of cytokines which are: i) anti-inflammatory, ii) produce counter-regulatory cytokines (e.g., IL-10, TGFBeta) that actively modulates Th1 responses, and iii) favor generation of immediate hypersensitivity responses (e.g. IgE and eosinophilia) that promote concomitant immunity. In addition, this proposal seeks to establish whether the duration and intensity of exposure to infective larvae and worm burdens are the major factors which determine Th2 dominance among MF subjects.